One in eight women will suffer breast cancer during their lifetime. About 70% of breast cancer depends on the presence of estrogen to grow, and is classified as Estrogen Receptor (ER) positive and estrogen dependent. ER regulates the expression of many genes, among which is Cyclin D1. Our recently research reported that EglN2, an estrogen inducible gene, positively regulates Cyclin D1 and contributes to breast tumorigenesis. The regulation of Cyclin D1 by EglN2 is largely depend on EglN2 prolyl hydroxylase activity. However, the mechanism underlying the regulation of Cyclin D1 by EglN2 remains largely unknown. In order to identify the potential EglN2 prolyl hydroxylase substrates that mediate this process, I performed in vitro hydroxylation screening for EglN2 substrates. FOXO3a was identified as a potential EglN2 target. I plan to validate FOXO3a as a novel EglN2 substrate (Aim 1) and examine whether FOXO3a mediates the effect of EglN2 on Cyclin D1, breast cancer cell proliferation in vitro and in vivo (Aim 2). Lastly, I will systematically search for FOXO3a direct transcription targets in EglN2-mediated breast tumorigenesis (Aim 3). The proposed research will elucidate the mechanism by which EglN2 mediates breast tumorigenesis and the important role of FOXO3a in this process.

Public Health Relevance

RELEVANCE: Our ability to develop targeted therapies against breast cancer is heavily dependent on a more detailed understanding of the molecular mechanism of EglN2-related breast tumorigenesis through generation and examination of accurate in vitro and in vivo model systems. This proposal will study the role of FOXO3a as the missing link by which EglN2 regulates Cyclin D1 and breast tumorigenesis. Successful completion of this proposal will motivate the development of EglN2 specific inhibitors as a means to induce FOXO3a to treat cancers, including breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA160351-05
Application #
8889207
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2013-02-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zhang, Jing; Wu, Tao; Simon, Jeremy et al. (2018) VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 361:290-295
Wang, Li; Wrobel, John A; Xie, Ling et al. (2018) Novel RNA-Affinity Proteogenomics Dissects Tumor Heterogeneity for Revealing Personalized Markers in Precision Prognosis of Cancer. Cell Chem Biol 25:619-633.e5
Takada, Mamoru; Zhang, Weiguo; Suzuki, Aussie et al. (2017) FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A. Cancer Res 77:4881-4893
Di Conza, Giusy; Trusso Cafarello, Sarah; Zheng, Xingnan et al. (2017) PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55?-Mediated Manner. Cell Rep 18:2836-2844
Takada, Mamoru; Zhuang, Ming; Inuzuka, Hiroyuki et al. (2017) EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor. Oncotarget 8:6787-6795
Zhang, Jing; Zheng, Xingnan; Zhang, Qing (2016) EglN2 positively regulates mitochondrial function in breast cancer. Mol Cell Oncol 3:e1120845
Zurlo, Giada; Guo, Jianping; Takada, Mamoru et al. (2016) New Insights into Protein Hydroxylation and Its Important Role in Human Diseases. Biochim Biophys Acta 1866:208-220
Zhang, Jing; Wang, Chengyang; Chen, Xi et al. (2015) EglN2 associates with the NRF1-PGC1? complex and controls mitochondrial function in breast cancer. EMBO J 34:2953-70
Lu, Gang; Zhang, Qing; Huang, Ying et al. (2014) Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell 26:222-34
Chen, Xi; Iliopoulos, Dimitrios; Zhang, Qing et al. (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1? pathway. Nature 508:103-107

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